title: Adult duct-lining cells can reprogram into β-like cells able to counter repeated cycles of toxin-induced diabetes.
abstract: It was recently demonstrated that embryonic glucagon-producing cells in the pancreas can regenerate and convert into insulin-producing β-like cells through the constitutive/ectopic expression of the Pax4 gene. However, whether α cells in adult mice display the same plasticity is unknown. Similarly, the mechanisms underlying such reprogramming remain unclear. We now demonstrate that the misexpression of Pax4 in glucagon(+) cells age-independently induces their conversion into β-like cells and their glucagon shortage-mediated replacement, resulting in islet hypertrophy and in an unexpected islet neogenesis. Combining several lineage-tracing approaches, we show that, upon Pax4-mediated α-to-β-like cell conversion, pancreatic duct-lining precursor cells are continuously mobilized, re-express the developmental gene Ngn3, and successively adopt a glucagon(+) and a β-like cell identity through a mechanism involving the reawakening of the epithelial-to-mesenchymal transition. Importantly, these processes can repeatedly regenerate the whole β cell mass and thereby reverse several rounds of toxin-induced diabetes, providing perspectives to design therapeutic regenerative strategies.
authors.affiliation: Université de Nice-Sophia Antipolis, FR-06108 Nice, France.
authors.forename: Keith
authors.initials: K
authors.lastname: Al-Hasani
authors.forename: Anja
authors.initials: A
authors.lastname: Pfeifer
authors.forename: Monica
authors.initials: M
authors.lastname: Courtney
authors.forename: Nouha
authors.initials: N
authors.lastname: Ben-Othman
authors.forename: Elisabet
authors.initials: E
authors.lastname: Gjernes
authors.forename: Andhira
authors.initials: A
authors.lastname: Vieira
authors.forename: Noémie
authors.initials: N
authors.lastname: Druelle
authors.forename: Fabio
authors.initials: F
authors.lastname: Avolio
authors.forename: Philippe
authors.initials: P
authors.lastname: Ravassard
authors.forename: Gunter
authors.initials: G
authors.lastname: Leuckx
authors.forename: Sandra
authors.initials: S
authors.lastname: Lacas-Gervais
authors.forename: Damien
authors.initials: D
authors.lastname: Ambrosetti
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Benizri
authors.forename: Jacob
authors.initials: J
authors.lastname: Hecksher-Sorensen
authors.forename: Pierre
authors.initials: P
authors.lastname: Gounon
authors.forename: Jorge
authors.initials: J
authors.lastname: Ferrer
authors.forename: Gerard
authors.initials: G
authors.lastname: Gradwohl
authors.forename: Harry
authors.initials: H
authors.lastname: Heimberg
authors.forename: Ahmed
authors.initials: A
authors.lastname: Mansouri
authors.forename: Patrick
authors.initials: P
authors.lastname: Collombat
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D001786:Blood Glucose / Q000032:analysis; D002454:Cell Differentiation; D019070:Cell Lineage; D002465:Cell Movement; D065150:Cellular Reprogramming; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D005786:Gene Expression Regulation; D050416:Glucagon-Secreting Cells / Q000378:metabolism / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006984:Hypertrophy / Q000378:metabolism / Q000473:pathology; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D051761:Paired Box Transcription Factors / Q000235:genetics / Q000378:metabolism; D010183:Pancreatic Ducts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013311:Streptozocin
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D001786:Blood Glucose; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D051761:Paired Box Transcription Factors; D013311:Streptozocin; C407737:Neurog3 protein, mouse; C110218:Pax4 protein, mouse